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Platelets from Asthmatic Individuals Show Less Reliance on Glycolysis.

Xu W, Cardenes N, Corey C, Erzurum SC, Shiva S - PLoS ONE (2015)

Bottom Line: Further, several studies demonstrate altered mitochondrial function in asthmatic airways and suggest that these changes may be systemic.However, it is unknown whether systemic metabolic changes can be detected in circulating cells in asthmatic patients.The implications for this potential metabolic shift will be discussed in the context of increased oxidative stress and hypoxic adaptation of asthmatic patients.

View Article: PubMed Central - PubMed

Affiliation: Lerner Research Institute, Cleveland, Ohio, United States of America.

ABSTRACT
Asthma, a chronic inflammatory airway disease, is typified by high levels of TH2-cytokines and excessive generation of reactive nitrogen and oxygen species, which contribute to bronchial epithelial injury and airway remodeling. While immune function plays a major role in the pathogenesis of the disease, accumulating evidence suggests that altered cellular metabolism is a key determinant in the predisposition and disease progression of asthma. Further, several studies demonstrate altered mitochondrial function in asthmatic airways and suggest that these changes may be systemic. However, it is unknown whether systemic metabolic changes can be detected in circulating cells in asthmatic patients. Platelets are easily accessible blood cells that are known to propagate airway inflammation in asthma. Here we perform a bioenergetic screen of platelets from asthmatic and healthy individuals and demonstrate that asthmatic platelets show a decreased reliance on glycolytic processes and have increased tricarboxylic acid cycle activity. These data demonstrate a systemic alteration in asthma and are consistent with prior reports suggesting that oxidative phosphorylation is more efficient asthmatic individuals. The implications for this potential metabolic shift will be discussed in the context of increased oxidative stress and hypoxic adaptation of asthmatic patients. Further, these data suggest that platelets are potentially a good model for the monitoring of bioenergetic changes in asthma.

No MeSH data available.


Related in: MedlinePlus

Platelets show less reliance on glycolysis in asthma.(A) Oxygen consumption trace for healthy (open squares) and asthmatic (filled squares). Basal rate is shown and arrows denote the addition of oligomycin A (oligo), FCCP, 2-deoxyglucose (2DG) and rotenone. (B) Quantification of basal rate, proton leak, ATP-linked respiration and non-mitochondrial oxygen consumption in platelets from healthy (open bars) and asthmatic (filled bars) subjects (calculated from traces such as those shown in panel A). (C) Quantification of oxygen consumption rate after the addition of 2-DG in healthy (open bars) and asthmatic (filled bars) platelets. (D) Changes in OCR as a function of ECAR in healthy (control; open circles) and asthmatic (Asthma; filled squares) platelets basally and after the addition of 2-DG. Arrows depict the shift after addition of 2-DG. Data are means ± SEM. #p<0.05. n = 12 for asthma, n = 13 for control.
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pone.0132007.g003: Platelets show less reliance on glycolysis in asthma.(A) Oxygen consumption trace for healthy (open squares) and asthmatic (filled squares). Basal rate is shown and arrows denote the addition of oligomycin A (oligo), FCCP, 2-deoxyglucose (2DG) and rotenone. (B) Quantification of basal rate, proton leak, ATP-linked respiration and non-mitochondrial oxygen consumption in platelets from healthy (open bars) and asthmatic (filled bars) subjects (calculated from traces such as those shown in panel A). (C) Quantification of oxygen consumption rate after the addition of 2-DG in healthy (open bars) and asthmatic (filled bars) platelets. (D) Changes in OCR as a function of ECAR in healthy (control; open circles) and asthmatic (Asthma; filled squares) platelets basally and after the addition of 2-DG. Arrows depict the shift after addition of 2-DG. Data are means ± SEM. #p<0.05. n = 12 for asthma, n = 13 for control.

Mentions: To determine whether bioenergetics were altered in platelets isolated from patients with asthma, oxygen consumption rate was first measured in platelets isolated from both groups. Basal oxygen consumption rate (OCR) of platelets was similar among groups [OCR pmol O2/min/106 platelets, control (n = 13) 47.8 ± 2.7, asthma (n = 12) 53.3 ± 6.0, P = 0.4] and respiratory rate was significantly decreased by the ATP synthase inhibitor oligomycin to a similar extent in both groups (Fig 3A). Treatment with rotenone, a pharmacological inhibitor of mitochondrial Complex I, affirmed that the OCR measured was predominantly mitochondrial with rotenone inhibiting 92±7% and 99.8±4% of oxygen consumption in platelets from asthma and control subjects respectively (Fig 3A and 3B). Analysis of this data demonstrates that there was no significant difference in ATP-linked respiration or proton leak between the two groups (Fig 3B). Notably, in the presence of deoxyglucose (2-DG), a competitive glucose analogue that inhibits glycolysis, oxygen consumption did not decrease in asthma, so that asthmatics had greater OCR than controls in the absence of glycolysis (Fig 3A and 3C). Fig 3D demonstrates this relationship between inhibition of glycolysis and the resulting drop in OCR observed in controls but not asthmatics. These data suggest that while asthmatic platelets are able to compensate for the inhibition of glycolysis-based ATP production, control platelets are more reliant on glycolysis, potentially due to substrate limitation.


Platelets from Asthmatic Individuals Show Less Reliance on Glycolysis.

Xu W, Cardenes N, Corey C, Erzurum SC, Shiva S - PLoS ONE (2015)

Platelets show less reliance on glycolysis in asthma.(A) Oxygen consumption trace for healthy (open squares) and asthmatic (filled squares). Basal rate is shown and arrows denote the addition of oligomycin A (oligo), FCCP, 2-deoxyglucose (2DG) and rotenone. (B) Quantification of basal rate, proton leak, ATP-linked respiration and non-mitochondrial oxygen consumption in platelets from healthy (open bars) and asthmatic (filled bars) subjects (calculated from traces such as those shown in panel A). (C) Quantification of oxygen consumption rate after the addition of 2-DG in healthy (open bars) and asthmatic (filled bars) platelets. (D) Changes in OCR as a function of ECAR in healthy (control; open circles) and asthmatic (Asthma; filled squares) platelets basally and after the addition of 2-DG. Arrows depict the shift after addition of 2-DG. Data are means ± SEM. #p<0.05. n = 12 for asthma, n = 13 for control.
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pone.0132007.g003: Platelets show less reliance on glycolysis in asthma.(A) Oxygen consumption trace for healthy (open squares) and asthmatic (filled squares). Basal rate is shown and arrows denote the addition of oligomycin A (oligo), FCCP, 2-deoxyglucose (2DG) and rotenone. (B) Quantification of basal rate, proton leak, ATP-linked respiration and non-mitochondrial oxygen consumption in platelets from healthy (open bars) and asthmatic (filled bars) subjects (calculated from traces such as those shown in panel A). (C) Quantification of oxygen consumption rate after the addition of 2-DG in healthy (open bars) and asthmatic (filled bars) platelets. (D) Changes in OCR as a function of ECAR in healthy (control; open circles) and asthmatic (Asthma; filled squares) platelets basally and after the addition of 2-DG. Arrows depict the shift after addition of 2-DG. Data are means ± SEM. #p<0.05. n = 12 for asthma, n = 13 for control.
Mentions: To determine whether bioenergetics were altered in platelets isolated from patients with asthma, oxygen consumption rate was first measured in platelets isolated from both groups. Basal oxygen consumption rate (OCR) of platelets was similar among groups [OCR pmol O2/min/106 platelets, control (n = 13) 47.8 ± 2.7, asthma (n = 12) 53.3 ± 6.0, P = 0.4] and respiratory rate was significantly decreased by the ATP synthase inhibitor oligomycin to a similar extent in both groups (Fig 3A). Treatment with rotenone, a pharmacological inhibitor of mitochondrial Complex I, affirmed that the OCR measured was predominantly mitochondrial with rotenone inhibiting 92±7% and 99.8±4% of oxygen consumption in platelets from asthma and control subjects respectively (Fig 3A and 3B). Analysis of this data demonstrates that there was no significant difference in ATP-linked respiration or proton leak between the two groups (Fig 3B). Notably, in the presence of deoxyglucose (2-DG), a competitive glucose analogue that inhibits glycolysis, oxygen consumption did not decrease in asthma, so that asthmatics had greater OCR than controls in the absence of glycolysis (Fig 3A and 3C). Fig 3D demonstrates this relationship between inhibition of glycolysis and the resulting drop in OCR observed in controls but not asthmatics. These data suggest that while asthmatic platelets are able to compensate for the inhibition of glycolysis-based ATP production, control platelets are more reliant on glycolysis, potentially due to substrate limitation.

Bottom Line: Further, several studies demonstrate altered mitochondrial function in asthmatic airways and suggest that these changes may be systemic.However, it is unknown whether systemic metabolic changes can be detected in circulating cells in asthmatic patients.The implications for this potential metabolic shift will be discussed in the context of increased oxidative stress and hypoxic adaptation of asthmatic patients.

View Article: PubMed Central - PubMed

Affiliation: Lerner Research Institute, Cleveland, Ohio, United States of America.

ABSTRACT
Asthma, a chronic inflammatory airway disease, is typified by high levels of TH2-cytokines and excessive generation of reactive nitrogen and oxygen species, which contribute to bronchial epithelial injury and airway remodeling. While immune function plays a major role in the pathogenesis of the disease, accumulating evidence suggests that altered cellular metabolism is a key determinant in the predisposition and disease progression of asthma. Further, several studies demonstrate altered mitochondrial function in asthmatic airways and suggest that these changes may be systemic. However, it is unknown whether systemic metabolic changes can be detected in circulating cells in asthmatic patients. Platelets are easily accessible blood cells that are known to propagate airway inflammation in asthma. Here we perform a bioenergetic screen of platelets from asthmatic and healthy individuals and demonstrate that asthmatic platelets show a decreased reliance on glycolytic processes and have increased tricarboxylic acid cycle activity. These data demonstrate a systemic alteration in asthma and are consistent with prior reports suggesting that oxidative phosphorylation is more efficient asthmatic individuals. The implications for this potential metabolic shift will be discussed in the context of increased oxidative stress and hypoxic adaptation of asthmatic patients. Further, these data suggest that platelets are potentially a good model for the monitoring of bioenergetic changes in asthma.

No MeSH data available.


Related in: MedlinePlus